AD Prevention Trials: An Industry Perspective

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1 AD Prevention Trials: An Industry Perspective Robert A. Lasser, MD, MBA Global Development Lead, Product Development Group Medical Director, Neurodegenerative Disorders F. Hoffmann - La Roche Ltd

2 Regulatory Precedent A4, TOMMorow, API Novartis (2E4) Attempts versus Success No approvals No gold standard/validation Scientific consensus as alternative Global perspective (agreement across HA, validation across cultures, etc) must be maintained Demonstrating value still requires multiple studies establishing a clear cognitivefunctional link for minimally important change in pre-dementia

3 Regulatory position: EMA draft guideline Limited confidence in existing regulatory path? Feasibility feasibility issues including length of the trial and number of drop-outs are recognized. Until a biomarker will be qualified as a reliable surrogate patients should be followed up for a sufficient time to capture relevant cognitive changes. Eligibility criteria the diagnostic construct of preclinical AD as well as the disease model in such an early stage still need to be validated. Population for prevention trials can be enriched. the relative contribution of each risk factor to the onset of the disease is not yet established and it is difficult to translate population risk at an individual level. Trial duration Prevention trials require large samples and long follow up, typically of at least 5 years. However, since scientific information to provide a firm regulatory framework for prevention trials is still lacking, no firm recommendation can be made and therefore scientific advice is recommended in case this is pursued. Endpoint(s) prevention of cognitive impairment no "gold standard Novel outcome tools not yet validated and cannot be endorsed solely as primary endpoints. time to event analysis could be a complementary measure. End of consultation (deadline for comments) 31 July

4 Unknowns of trial design in preclinical AD An unattractive prospect for industry? Feasibility Patient access and willingness to participate (for many years) Anticipated attrition rates Sample size Eligibility criteria Reliability of biomarkers Enrichment for progression Trial duration Even longer than current pad stage trials (5+ years) Endpoint(s) Continuous Versus Time to Event Regulatory perspective on defining Clinically Evident Decline, Disability or other event Culturally bound Product Label What (differentiated) label might be achieved Eventual Market Infrastructure issues on screening and treatment Who to treat and when (relative cost and invasive nature of existing biomarkers prohibitive of large scale adoption) Willingness to treat otherwise healthy individuals (for life) and bear cost Current ability to demonstrate cost savings to health care systems (already a challenge for MCI due to AD/pAD stage) 4

5 The path forward Cross-industry consortia DIAN Alzheimer s Prevention Initiative Treatment Trials Opportunity to explore and validate trial design and feasibility questions without bearing full risk Provides an impetus to shift regulatory science 5

6 DIAN-TU Cognitive Battery Considerations in the selection of cognitive tests: 1. Some overlap with the DIAN observational study to allow for comparison and provide continuity 2. Sufficient published validation literature, widely used in pharmaceutical research, and covering main domains of cognition affected by AD 3. Some overlap with measures used in other secondary prevention trials (A4, API and TOMMorrow), so that results can be compared 4. Ease of administration and participant acceptability 6

7 API composite cognitive test score Creation of composite Used longitudinal data from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers Mean-to-standard-deviation ratios of change over time calculated in search for optimal combination of 1 to 7 cognitive tests/subtests Combinations that performed well evaluated for: Robustness across follow-up Occurrence of items within top-performing combinations Representation of relevant cognitive domains Optimal test combination included: CERAD Word List Recall CERAD Boston Naming Test (high frequency items) Mini-Mental State Examination (MMSE) Orientation to Time CERAD Constructional Praxis Raven's Progressive Matrices (Set A) Ayutyanont et al,

8 Summary of cognitive tests used in the four main secondary prevention clinical trials of AD DIAN-TU A4 API TOMMorrow Memory Executive Function Language Attention Visuospatial Paper & Pencil Computerized Paper & Pencil Computerized Paper & Pencil Computerized Paper & Pencil Computerized WMS-R Logical International WMS-R Logical Face-Name 10 Word Delayed CVLT-II Memory Shopping List Test Memory Associative Recall Memory Task Raven s Progressive Matrices (12) Digit Span Backward Trail Making B Semantic fluency (Vegetables) Semantic fluency (Animals) Lexical/Phonemic Fluency (FAS) WAIS-R Digit Symbol Digit Span Forward Cogstate One Card Learning Cogstate One Back Object Pattern Separation Task Groton Maze Learning Test Groton Maze Learning Test Cogstate Detection Cogstate Identification Timed Chase Test 16-item Free & Cued SRT WAIS-R Digit Symbol Cogstate One Card Learning Cogstate One Back Object Pattern Separation Task Cogstate Detection Cogstate Identification Raven s Progressive Matrices (9) Multilingual Naming Test CERAD Constructional Praxis Global MMSE MMSE MMSE (Orientation) Other CDR CDR MAC-Q MAC-Q Brief Visuospatial Memory Test-R Trail Making B Digit Span Backward Multilingual Naming Test Semantic Fluency (Animals) Lexical/Phonemic Fluency (FAS) Trail Making A Digit Span Forward BVMT-R Figures (copy) Clock Drawing 8

9 Considerations for cognitive test batteries What is the correct way to select amongst feasible component tests Clinical presentation of MCI due to AD/prodromal AD? Statistical modelling for optimal signal to noise ratio in measuring disease progression? Patient/caregiver insights into disease burden/impact? Modern psychometrics (IRT)? Association to functional impairment? Ultimately, what is the underlying concept(s) we are attempting to measure? 9

10 Doing now what patients need next